A salient pathological feature of Alzheimer's disease (AD) is the presence of amyloid plaques in the brains of affected patients. The plaques are predominantly composed of human β-amyloid peptide (Aβ). Although the aggregation of synthetic Aβ has been extensively studied, the mechanism of AD plaque growth is poorly understood. In order to address this question, we used an in vitro model of plaque growth to determine if assembly or aggregation of Aβ is required for deposition. Labeled Aβ at physiological concentrations readily deposited onto both neuritic and diffuse plaques and cerebrovascular amyloid in unfixed AD brain tissue, whereas essentially no deposition was detected in tissue without preformed amyloid. Using this in vitro model of plaque growth, the kinetics of Aβ deposition onto plaques was examined in two independent but complementary systems. Intact sections of unfixed AD brain cortex (analyzed by autoradiographic densitometry) allowed definitive morphological analysis of the site of deposition, while homogenates of the same tissue (analyzed by radioisotope counting) allowed precise quantitation of deposition over a wide range of conditions. Essentially identical results were obtained for both systems. Growth of preexisting tissue plaques by deposition of Aβ was found to follow first-order dependence on Aβ concentration and exhibited a pH optimum of 7. In sharp contrast, Aβ aggregation in the absence of template follows higher order kinetics and shows a pH optimum of 5. On the basis of criteria of kinetic order, pH dependence, and structure - activity relationships, we conclude that aggregation of Aβ (template-independent initial nidus formation) and deposition of Aβ (template-dependent subsequent plaque growth) are fundamentally distinct biochemical processes. The process of plaque growth and maturation by Aβ deposition may be an important target for therapeutic intervention to block the progression of AD.
|Original language||English (US)|
|Number of pages||9|
|State||Published - Jan 23 1996|
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